The dual abuse of cocaine and heroin (commonly called "speedballs") is a pernicious form of drug addiction that has increased worldwide along with the increased availability of cocaine and heroin. Speedball abusers show a higher rate of failure in treatment, a greater incidence of psychopathology, and increased risk of HIV infection compared to abusers of the individual drugs. Despite the prevalence and detrimental consequences of speedball abuse, comparatively little is known about its neuropharmacological basis or treatment. Our previous research using nonhuman primate models of the subjective and reinforcing effects of drugs has revealed a distinctive pattern of interactions between cocaine and heroin, which appears to be mediated via mu and delta opioid and D1-like and D2-like dopamine receptor mechanisms. Our proposed research will build on these findings by investigating the role of specific receptor subtypes within these receptor families. In rhesus monkeys trained to discriminate IV cocaine from vehicle or to self-administer IV cocaine under a modified progressive-ratio schedule, we will use selective agonists and antagonists to investigate the contribution of subtypes of mu and delta receptors in heroin-induced enhancement of the discriminative stimulus and reinforcing effects of cocaine. In rhesus monkeys trained to discriminate IV heroin from vehicle or to self-administer IV heroin under a modified progressive-ratio schedule, we will use a similar strategy to investigate the contribution of D1-like and subtypes of D2-like receptors in cocaine-induced attenuation of the discriminative stimulus effects of heroin and cocaine-induced enhancement of the reinforcing effects of heroin. Quantitative pharmacological analyses, including in vivo apparent pA2 and isobolographic analysis, along with a novel behavioral economic model termed labor-supply will provide an objective framework for interpretation of drug interactions. The results of our proposed research will provide needed information about neuropharmacological mechanisms underlying speedball addiction and potential targets for medication development.